ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.11241C>A (p.Tyr3747Ter) (rs777465132)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000710334 SCV000840528 pathogenic Usher syndrome 2018-09-17 reviewed by expert panel curation The p.Tyr3747X variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 58/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). The allele frequency of the p.Tyr3747X variant in the Ush2A gene is 0.017% (4/24020) of African chromosomes by the Genome Aggregation Database (, which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss ( PM2_Supporting). This variant has been detected in 1 patient with hearing loss in trans with a suspected pathogenic variant (PM3_Supporting, Partners LMM internal data SCV000713838.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied: PVS1, PM2_Supporting, PM3_Supporting.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000605356 SCV000713838 pathogenic Rare genetic deafness 2018-01-30 criteria provided, single submitter clinical testing The p.Tyr3747X variant in USH2A has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 0.02% (4/24020) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad; dbSNP rs777465132). This nonsense variant leads to a premat ure termination codon at position 3747, which is predicted to lead to a truncate d or absent protein. Variants in USH2A resulting in a loss of function of the pr otein is an established disease mechanism in autosomal recessive Usher syndrome. In addition, this variant is likely in trans with the deletion of exons 63-64 i n USH2A given that previous cases with the deletion did not carry this variant. This provides additional evidence that the variant is pathogenic. In summary, th is variant meets our criteria to be classified as pathogenic for autosomal reces sive Usher syndrome. ACMG/AMP Criteria applied: PVS1; PM2; PM3.
Invitae RCV001057761 SCV001222271 pathogenic not provided 2019-12-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr3747*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs777465132, ExAC 0.02%). This nonsense change has been observed in individual(s) with inherited retinal dystrophy (PMID: 30337596). ClinVar contains an entry for this variant (Variation ID: 506273). Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001057761 SCV001803549 pathogenic not provided 2019-08-27 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV001271137 SCV001451990 pathogenic Usher syndrome, type 2A 2020-09-16 no assertion criteria provided clinical testing

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